Possible effect of genetic background in thrombophilia genes on clinical severity of patients with coronavirus disease-2019: A prospective cohort study
Keywords:COVID-19, FVL, MTHFR, PAI-1, polymorphism, thrombophilia
Background and objective: Thrombotic and microangiopathic effects have been reported in Coronavirus Disease-2019 (COVID-19) patients. In the present study, we aimed to examine the relationship between hereditary thrombophilia factors and the clinical picture severity of COVID-19 patients.
Methods: Ninety COVID-19 patients were included and grouped according to the severity to three groups: severe/critical (n=30), mild/moderate (n=30) and asymptomatic (n=30). Hereditary thrombophilia genetic markers [prothrombin (FII) G20210A, factor V Leiden (FVL) G1691A, factor XIII (FXIII) V34L, methylene tetrahydrofolate reductase (MTHFR) A1298C and C677T, and plasminogen activator inhibitor-1 (PAI-1) 4G & 5G] were genotyped for all patients.
Results: Seventeen (18.9%) patients had the polymorphism 4G/4G PAI-1 and 48 (53.3%) had 4G/5G. In addition, the heterozygous GA FVL, MTHRF677CT, and MTHRF1298AC polymorphisms were detected in 11 (12.2%), 26 (28.9%), and 38 (42.2%) patients, respectively. The rate of severe/critical patients with PAI 4G/5G gene polymorphism was higher than the asymptomatic+moderate/mild patients, and the rate of severe/critically ill patients with PAI 4G/4G polymorphism was found to be lower than the asymptomatic+moderate/mild patients. No difference was evidenced between the distribution of deceased and survivors of the genotype groups.
Conclusions: In the present study, we found that heterozygous 4G/5G PAI-1 polymorphism is associated with critical or severe COVID-19 picture, and that FVL, MTHFR, FXIII, and prothrombin polymorphisms were not directly related to COVID-19 severity.
A Girolami et al. “Prothrombin: Another clotting factor after FV that is involved both in bleeding and thrombosis”. Clin Appl Thromb Hemost 24(6) (2018), pp. 845–849. DOI: 10.1177/1076029618770741.
A K Ghosh and D E Vaughan. “PAI-1 in tissue fibrosis”. J Cell Physiol 227(2) (2012), pp. 493–507. DOI: 10.1002/jcp.22783.
A Kiraz et al. “Investigation of the relationship between inherited thrombophilia and novel coronavirus pneumonia”. Future Virol 16(5) (2021), pp. 341–345. DOI: 10.2217/fvl-2020-0395.
B L Levin and E Varga. “MTHFR: Addressing genetic counseling dilemmas using evidence-based literature”. J Genet Couns 25(5) (2016), pp. 901–911. DOI: 10.1007/s10897-016-9956-7.
D E Vaughan. “PAI-1 and atherothrombosis”. J Thromb Haemost 3(8) (2005), pp. 1879–1883. DOI: 10.1111/j.1538-7836.2005.01420.x.
D Giannis, I A Ziogas, and P Gianni. “Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past”. J Clin Virol 127 (2020), pp. 104362–104362. DOI: 10.1016/j.jcv.2020.104362.
D Wu and X O Yang. “Dysregulation of pulmonary responses in severe COVID-19”. Viruses 13(6) (2021). DOI: 10.3390/v13060957.
E Campello et al. “Factor V Leiden paradox and the occurrence of distal vein thrombosis in a large cohort of thrombotic patients”. Thromb Res 156 (2017), pp. 20–22. DOI: 10.1016/j.thromres.2017.05.025.
E H Federici and H Al-Mondhiry. “High risk of thrombosis recurrence in patients with homozygous and compound heterozygous factor V R506Q (Factor V Leiden) and prothrombin G20210A”. Thromb Res 182 (2019), pp. 75–78. DOI: 10.1016/j.thromres.2019.07.030.
F Zhou, T Yu, R Du, et al. “Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study”. Lancet 395(10229) (2020), pp. 1054–1062. DOI: 10.1016/S0140-6736(20)30566-3.
H A Rothan and S N Byrareddy. “The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak”. J Autoimmun 109 (2020), pp. 102433–102433. DOI: 10.1016/j.jaut.2020.102433.
J A Stefely, B B Christensen, T Gogakos, et al. “Marked factor V activity elevation in severe COVID-19 is associated with venous thromboembolism”. Am J Hematol 95(12) (2020). DOI: 10.1002/ajh.25979.
J Altinisik et al. “Factor V Leiden, prothrombin G20210A, and protein C mutation frequency in Turkish venous thrombosis patients”. Clin Appl Thromb Hemost 14(4) (2008), pp. 415–420. DOI: 10.1177/1076029607306404.
J M Connors. “Thrombophilia testing and venous thrombosis”. N Engl J Med 377(12) (2017), pp. 1177–1187. DOI: 10.1056/NEJMra1700365.
L Xie, Q Wu, Q Lin, et al. “Dysfunction of adaptive immunity is related to severity of COVID-19: a retrospective study”. Ther Adv Respir Dis 14 (2020), pp. e1753466620942129. DOI: 10.1177/1753466620942129.
M Karimi, S Haghpanah, and A Shahsavani. “Prevalence and clinical features of COVID-19 in Iranian patients with congenital coagulation disorders”. Blood Transfus 18(5) (2020), pp. 413–414. DOI: 10.2450/2020.0223-20.
M Karst, J Hollenhorst, and J Achenbach. “Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolic acid reductase (MTHFR) polymorphism and hyperhomocysteinemia?” Med Hypotheses 144 (2020), pp. 110234–110234. DOI: 10.1016/j.mehy.2020.110234.
M Panigada, N Bottino, P Tagliabue, et al. “Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis”. J Thromb Haemost 18(7) (2020), pp. 1738–1742. DOI: 10.1111/jth.14850.
N Kipshidze, G Dangas, C J White, et al. “Viral coagulopathy in patients with COVID-19: Treatment and care”. Clin Appl Thromb Hemost 26 (2020), pp. 1076029620936776–1076029620936776.
R Liu, Y Wang, J Li, et al. “Decreased T cell populations contribute to the increased severity of COVID-19”. Clin Chim Acta 508 (2020), pp. 110–114. DOI: 10.1016/j.cca.2020.05.019.
R M Camire. “A new look at blood coagulation factor V”. Curr Opin Hematol 18(5) (2011), pp. 338–342. DOI: 10.1097/MOH.0b013e3283497ebc.
Republic of Turkey Ministry of Health. COVID-19 (SARS-CoV-2 Infection): Scientific Committee Study. 2020. URL: https://www.teb.org.tr/versions_latest/1240/13nisansbrehberi.
S Cui et al. “Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia”. J Thromb Haemost 18(6) (2020), pp. 1421–1424. DOI: 10.1111/jth.14830.
S Duga, R Asselta, and M L Tenchini. “Coagulation factor V”. Int J Biochem Cell Biol 36(8) (2004), pp. 1393–1399. DOI: 10.1016/j.biocel.2003.08.002.
S Lancellotti, Maria Basso, and Raimondo De Cristofaro. “Congenital prothrombin deficiency: an update”. Semin Thromb Hemost 35(4) (2009), pp. 367–381. DOI: 10.1055/s-0033-1348948.
S Middeldorp, M Coppens, T F Van Haaps, et al. “Incidence of venous thromboembolism in hospitalized patients with COVID-19”. J Thromb Haemost 18(8) (2020), pp. 1995–2002. DOI: 10.1111/jth.14888.
S Wan, Q Yi, S Fan, et al. “Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients”. Br J Haematol 189(3) (2020), pp. 428–437. DOI: 10.1111/bjh.16659.
T Iwaki, T Urano, and K Umemura. “PAI-1, progress in understanding the clinical problem and its aetiology”. Br J Haematol 157(3) (2012), pp. 291–298. DOI: 10.1111/j.1365-2141.2012.09074.x.
T Matsuyama et al. “An aberrant STAT pathway is central to COVID-19”. Cell Death Differ 27(12) (2020), pp. 3209–3225. DOI: 10.1038/s41418-020-00633-7.
Y Zhang, W Cao, W Jiang, et al. “Profile of natural anticoagulant, coagulant factor and anti-phospholipid antibody in critically ill COVID-19 patients”. J Thromb Thrombolysis 50(3) (2020), pp. 580–586. DOI: 10.1007/s11239-020-02182-9.
Y Zhou, V Sinnathamby, Y Yu, et al. “Folate intake, markers of folate status and oral clefts: An updated set of systematic reviews and meta-analyses”. Birth Defects Res 112 (2019), pp. 1699–1719. DOI: 10.1002/bdr2.1827.
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